WO1996011930A1 - Derives de pyridinyluree actifs dans le traitement des troubles du systeme nerveux central - Google Patents

Derives de pyridinyluree actifs dans le traitement des troubles du systeme nerveux central Download PDF

Info

Publication number
WO1996011930A1
WO1996011930A1 PCT/EP1995/003944 EP9503944W WO9611930A1 WO 1996011930 A1 WO1996011930 A1 WO 1996011930A1 EP 9503944 W EP9503944 W EP 9503944W WO 9611930 A1 WO9611930 A1 WO 9611930A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
alkyl
compound
hydrogen
group
Prior art date
Application number
PCT/EP1995/003944
Other languages
English (en)
Inventor
Ian Thomson Forbes
Graham Elgin Jones
Original Assignee
Smithkline Beecham P.L.C.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham P.L.C. filed Critical Smithkline Beecham P.L.C.
Priority to EP95934135A priority Critical patent/EP0788499A1/fr
Priority to JP8512907A priority patent/JPH10508584A/ja
Publication of WO1996011930A1 publication Critical patent/WO1996011930A1/fr
Priority to US08/817,580 priority patent/US5866586A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • This invention relates to compounds having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS disorders.
  • WO94/04533 (SmithKline Beecham plc) describes indole and indoline derivatives which are described as possessing 5HT 2C receptor antagonist activity.
  • a structurally distinct class of compounds has now been discovered, which have been found to have 5HT 2C receptor antagonist activity. Some or all of the compounds of the invention also exhibit 5HT 2B antagonist activity.
  • 5HT 2B/2C receptor antagonists are believed to be of potential use in the treatment of CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, Alzheimers disease, sleep disorders, feeding disorders such as anorexia and bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus.
  • Compounds of the invention are also expected to be of use in the treatment of certain GI disorders such as IBS as well as microvascular diseases such as macular oedema and retinopathy.
  • the present invention therefore provides, in a first aspect, a compound of formula (I) or a salt thereof:
  • P represents phenyl, a quinoline or isoquinoline residue, or a 5-membered or 6-membered aromatic heterocyclic ring containing up to three heteroatoms selected from nitrogen, oxygen or sulphur;
  • R 1 is hydrogen, C 1-6 alkyl, C 1-6 alkylthio, cyano, nitro, halogen, CF 3 , NR 8 R 9 , CONR 8 R 9 , CO 2 R 10 or OR 10 where R 8 , R 9 and R 10 are independently hydrogen, C 1-6 alkyl or arylC 1-6 alkyl;
  • R 2 is hydrogen or C 1-6 alkyl
  • R 3 is a group of formula (i): in which:
  • X and Y are both nitrogen or one is nitrogen and the other is carbon or a CH group;
  • R 4 and Regroups are independently C 1-6 alkyl optionally substituted by one or more halogen atoms, C 2-6 alkenyl, C 3-6 cycloalkyloxy, C 3-6 cycloalkylC 1-6 alkoxy, C 2-6 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 1-6 alkylthio,
  • R 4 and R 5 form part of an optionally substituted 5-membered carbocyclic or heterocyclic ring
  • R 6 and R 7 are independently hydrogen or C 1-6 alkyl
  • R 3 is a group of formula (ii):
  • R 4 and R 5 are as defined in formula (i), X and Y are both nitrogen or one is nitrogen and the other is a CH group;
  • R 12 is hydrogen or C 1-6 alkyl.
  • C 1-6 alkyl groups may be straight chain or branched.
  • the urea moiety can be attached to a carbon or any available nitrogen atom of the ring P, preferably it is attached to a carbon atom. Suitable moieties when the ring
  • P is a 5-membered aromatic heterocyclic ring include isothiazolyl, isoxazolyl, thiadiazolyl and triazolyl.
  • Suitable moieties when the ring P is a 6-membered aromatic heterocyclic ring include, for example, pyridyl, pyrimidyl or pyrazinyl.
  • P is quinoline, or an isoquinoline residue, the urea moiety can be attached at any position of the ring, preferably to the 4- or 5-position.
  • P is 3-pyridyl.
  • R 1 is hydrogen
  • R 2 is hydrogen
  • R 3 is a group of formula (i) where R 6 and R 7 are hydrogen and X is carbon or a CH group and Y is nitrogen.
  • R 4 is trifluoromethyl or halogen. Most preferably R 4 is halogen, in particular chloro.
  • R 5 is C 1-6 alkylthio, in particular thiomethyl, or C 1-6 alkoxy, in particular methoxy. Most preferably R 4 is thiomethyl.
  • suitable rings include thiophene, furan and pyrrole rings.
  • Optional subtituents for such rings include C 1-6 alkyl groups, for example methyl.
  • Particular compounds of the invention include:
  • the compounds of the formula (I) can form acid addition salts with acids, such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicyclic, citric, lactic, mandelic, tartaric and methanesulphonic.
  • acids such as conventional pharmaceutically acceptable acids, for example maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicyclic, citric, lactic, mandelic, tartaric and methanesulphonic.
  • Certain compounds of formula (I) may also form N-oxides or solvates such as hydrates, and the invention also extends to these forms.
  • the term 'compound of formula (I)' also includes these forms.
  • the present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises:
  • R 1' , R 2' and R 3 are R 1 , R 2 and R 3 respectively, as defined in formula (I), or groups convertible thereto, and thereafter optionally and as necessary and in any appropriate order, converting any R 1' , R 2' and R 3 ', when other than R 1 , R 2 and R 3 respectively to R 1 , R 2 and R 3 , interconverting R 1 , R 2 and R 3 and forming a pharmaceutically acceptable salt thereof.
  • Suitable examples of groups A and B include;
  • A is -NR 2' COL and B is hydrogen
  • A is -NHR 2' and B is COL, or
  • R 2 is as defined above and L is a leaving group.
  • suitable leaving groups L include halogen such as chloro, bromo, imidazole, phenoxy or phenylthio optionally substituted, for example, with halogen.
  • reaction is suitably carried out in an inert solvent for example dichloromethane or toluene at ambient or elevated temperature.
  • reaction is suitably carried out in an inert solvent such as dichloromethane at ambient temperature optionally in the presence of a base, such as triethylamine or in dimethylformamide at ambient or elevated temperature.
  • an inert solvent such as dichloromethane at ambient temperature
  • a base such as triethylamine or in dimethylformamide at ambient or elevated temperature.
  • reaction is suitably carried out in an inert solvent such as toluene at elevated temperature, optionally in the presence of a base.
  • P in formula (I) represents rings P as defined in relation to formula (I) in which R 1 is as defined in relation to formula (I) or groups convertible thereto i.e. R 1' .
  • R 4 and R 5 groups can be introduced at any suitable stage in the process, preferably R 4 and R 5 groups are introduced at any early stage in the process. It should be appreciated that it is preferred that the groups R 1 , R 2 , R 4 and R 5 are introduced before coupling compounds of formula (II) and (III).
  • Suitable examples of groups convertible to alkyl groups include acyl groups which are introduced conventionally and may be converted to the corresponding alkyl group by conventionally reduction, such as using sodium borohydride in an inert solvent followed by hydrogenolysis in an inert solvent. Hydrogen substituents may be obtained from alkoxycarbonyl groups which may be convened to hydrogen by hydrolysis and decarboxylation.
  • Suitable examples of a group R 2' which are convertible to R 2 include alkoxycarbonyl and benzyl or para-methoxybenzyl which are converted to the group where R 2 is hydrogen using conventional conditions.
  • R 1 halo may be introduced by selective halogenation of the ring P using conventional conditions. It should be appreciated that it may be necessary to protect any hydrogen variables which are not required to be interconverted.
  • Suitable protecting groups and methods for their attachment and removal are conventional in the art of organic chemistry, such as those described in Green T.W. 'Protective groups in organic synthesis' New York, Wiley (1981).
  • A is amino, which phosgene or a phosgene equivalent, in the presence of excess base in an inen solvent.
  • A is acylazide (i.e. CON 3 ), via the nitrene, by thermal rearrangement using conventional conditions (ref L.S. Trifonov et al, Helv. Chim. Acta 1987 70 262).
  • A is CONH 2 , via the nitrene intermediate using conventional conditions.
  • Compounds of formula (II) in which A is NR 21 COL may be prepared by reacting a compound of formula (II) in which A is NHR 2 with phosgene or a phosgene equivalent in an inert solvent, at low temperature, if necessary in the presence of one equivalent of a base such as trithylamine.
  • R 3 ' is a group of formula (i), from the appropriate pyridine carboxylic acid via azide formation and conversion to the corresponding isocyanate.
  • R 3 is a group of formula (ii), from the appropriate nitropyridine the substitution of an ortho position with a functionalised alkyl group.
  • Novel intermediates of formula (III) also form part of the invention.
  • salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.
  • N-oxides may be formed conventionally by reaction with hydrogen peroxide or percarboxylic acids.
  • Compound of formula (I) and their pharmaceutically acceptable salts have 5HT 2B/2C receptor antagonist activity and are believed to be of potential use in the treatment or prophylaxis of CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, Alzheimers disease, sleep disorders, feeding disorders such as anorexia and bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus.
  • Compounds of the invention are also expected to be of use in the treatment of certain GI disorders such as IBS as well as microvascular diseases such as macular oedema and retinopathy.
  • the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance, in particular in the treatment or prophylaxis of the above disorders.
  • the invention further provides a method of treatment or prophylaxis of the above disorders, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of the above disorders.
  • the present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof., and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition of the invention which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges,
  • reconstitutable powders injectable or infusable solutions or suspensions or suppositories.
  • Orally administerable compositions are generally preferred.
  • Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants.
  • fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealant.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • composition may contain from 0.1% to 99% by weight, preferably from 10% to 66% by weight, of the active material, depending on the method of administration.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 20.0 mg, for example 0.2 to 5 mg; and such unit doses may be administered more than once a day, for example two or three a day, so that the total daily dosage is in the range of about 0.5 to 100 mg; and such therapy may extend for a number of weeks or months.
  • N-3-[5-Chloro-4-(2-hydroxyethyl)-6-methylthio]pyridyl-N'-(3-pyridyl)urea Nicotinoyl azide (0.274g, 1.85 mmol) was dissolved in toluene (10 ml) and heated to reflux. After 1 ⁇ 2 h the reaction mixture was allowed to cool and was added to a stirred solution of 5-amino-3-chloro-4-(2-hydroxyethyl)-2-methylthiopyridine (D8) (0.370g, 0.67 mmol) in dichloromethane (50 ml). After 1 h, the dichloromethane was removed by evaporation under reduced pressure and the resultant precipitate was filtered off and dried in vacuo to give the tide compound as a cream solid (0.438g, 77%).
  • N-3-[5-chloro-4-(2-hydroxyethyl)-6-methylthio]pyridyl-N'-(3-pyridyl)urea (D9) (0.438g, 1.29 mmol) was suspended in dry THF (45 ml) with stirring under argon, and was treated with triphenylphosphine (0.338g, 1.29 mmol) and diethyl
  • the compounds of examples 1 to 3 have pKi values in the range 7.4 to 8.1.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Anesthesiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

L'invention se rapporte à des composés hétérocycliques de la formule (I) qui présentent une activité pharmacologique, à leurs procédés de préparation, aux compositions les contenant et à leur utilisation dans le traitement des troubles du système nerveux central, formule (I) dans laquelle P représente phényle, un reste de quinoline ou d'isoquinoline, ou un noyau hétérocyclique aromatique pentagonal ou hexagonal contenant jusqu'à trois hétéroatomes sélectionnés parmi l'azote, l'oxygène ou le soufre; R3 représente un groupe de la formule (i) ou (ii).
PCT/EP1995/003944 1994-10-18 1995-10-05 Derives de pyridinyluree actifs dans le traitement des troubles du systeme nerveux central WO1996011930A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP95934135A EP0788499A1 (fr) 1994-10-18 1995-10-05 Derives de pyridinyluree actifs dans le traitement des troubles du systeme nerveux central
JP8512907A JPH10508584A (ja) 1994-10-18 1995-10-05 Ｃｎｓ活性ピリジニル尿素誘導体
US08/817,580 US5866586A (en) 1994-10-18 1997-10-05 CNS-active pyridinylurea derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9420999.6 1994-10-18
GB9420999A GB9420999D0 (en) 1994-10-18 1994-10-18 Novel compounds

Publications (1)

Publication Number Publication Date
WO1996011930A1 true WO1996011930A1 (fr) 1996-04-25

Family

ID=10763030

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1995/003944 WO1996011930A1 (fr) 1994-10-18 1995-10-05 Derives de pyridinyluree actifs dans le traitement des troubles du systeme nerveux central

Country Status (5)

Country Link
US (1) US5866586A (fr)
EP (1) EP0788499A1 (fr)
JP (1) JPH10508584A (fr)
GB (1) GB9420999D0 (fr)
WO (1) WO1996011930A1 (fr)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6022884A (en) * 1997-11-07 2000-02-08 Amgen Inc. Substituted pyridine compounds and methods of use
WO2000076984A2 (fr) * 1999-05-21 2000-12-21 Biovitrum Ab Nouveaux composes, et utilisation et preparation de ces derniers
FR2810979A1 (fr) * 2000-06-29 2002-01-04 Adir Nouveaux derives de diphenyluree, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
US6362009B1 (en) 1997-11-21 2002-03-26 Merck & Co., Inc. Solid phase synthesis of heterocycles
WO2002040457A1 (fr) 2000-11-20 2002-05-23 Biovitrum Ab Composes de piperazinylpyrazines utilises comme antagonistes du recepteur de la serotonine 5-ht2
US6410561B1 (en) 1998-03-26 2002-06-25 Japan Tobacco Inc. Amide derivatives and nociceptin antagonists
US6465467B1 (en) 1999-05-21 2002-10-15 Biovitrum Ab Certain aryl-aliphatic and heteroaryl-aliphatic piperazinyl pyrazines and their use in the treatment of serotonin-related diseases
JP2003502317A (ja) * 1999-05-21 2003-01-21 ビオヴィトルム・アクチボラゲット 新規化合物、その使用および製造
US6756377B2 (en) 2000-11-20 2004-06-29 Biovitrum Ab Compounds and their use
US7056925B2 (en) 2002-08-13 2006-06-06 Abbott Laboratories Urea kinase inhibitors
US7067506B2 (en) * 2001-03-02 2006-06-27 Icos Corporation Compounds useful for inhibiting Chk1
US7291603B2 (en) 2002-07-24 2007-11-06 Ptc Therapeutics, Inc. Nucleoside compounds and their use for treating cancer and diseases associated with somatic mutations
EP2036564A1 (fr) 1999-12-06 2009-03-18 H.Lundbeck A/S Combinaison d'un inhibiteur du recaptage de la serotonine et d'un antagoniste, d'un agoniste inverse ou d'un agoniste partiel de 5-ht
US9266883B2 (en) 2013-10-25 2016-02-23 Novartis Ag Ring-fused bicyclic pyridyl derivatives as FGFR4 inhibitors
US9463295B2 (en) 1996-07-26 2016-10-11 Resmed Limited Mask and mask cushion therefor
US9802917B2 (en) 2015-03-25 2017-10-31 Novartis Ag Particles of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide
US9951069B1 (en) 2017-01-11 2018-04-24 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US10421756B2 (en) 2015-07-06 2019-09-24 Rodin Therapeutics, Inc. Heterobicyclic N-aminophenyl-amides as inhibitors of histone deacetylase
US10919902B2 (en) 2015-07-06 2021-02-16 Alkermes, Inc. Hetero-halo inhibitors of histone deacetylase
US11225475B2 (en) 2017-08-07 2022-01-18 Alkermes, Inc. Substituted pyridines as inhibitors of histone deacetylase

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8715066B2 (en) 2010-06-14 2014-05-06 Automated Cash Systems, Llc System and method for electronic fund transfers for use with gaming systems
EP3200786B1 (fr) 2014-10-03 2019-08-28 Novartis AG Utilisation de dérivés pyridyle bicycliques à anneaux fusionnés en tant qu'inhibiteurs de fgfr4

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994004533A1 (fr) * 1992-08-20 1994-03-03 Smithkline Beecham Plc DERIVES D'INDOLE CONDENSES UTILISES COMME ANTAGONISTES DES RECEPTEURS 5HT2C et 5HT¿2B?
WO1994014801A1 (fr) * 1992-12-29 1994-07-07 Smithkline Beecham Plc Derives heterocycliques de l'uree antagonistes de 5ht2c et 5h¿2b?
WO1994018972A2 (fr) * 1993-02-25 1994-09-01 Warner-Lambert Company Procedes permettant de traiter des maladies et troubles neurodegeneratifs avec des urees n-(2,6-aromatiques disubstitues)-n'-pyridinyle et d'autres composes anticonvulsivants

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994004533A1 (fr) * 1992-08-20 1994-03-03 Smithkline Beecham Plc DERIVES D'INDOLE CONDENSES UTILISES COMME ANTAGONISTES DES RECEPTEURS 5HT2C et 5HT¿2B?
WO1994014801A1 (fr) * 1992-12-29 1994-07-07 Smithkline Beecham Plc Derives heterocycliques de l'uree antagonistes de 5ht2c et 5h¿2b?
WO1994018972A2 (fr) * 1993-02-25 1994-09-01 Warner-Lambert Company Procedes permettant de traiter des maladies et troubles neurodegeneratifs avec des urees n-(2,6-aromatiques disubstitues)-n'-pyridinyle et d'autres composes anticonvulsivants

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
B. STANOVNIK EZ AL: "Heteroacyl azides as acylating agents for aromatic or heteroaromatic amines", JOURNAL OF HETEROCYCLIC CHEMISTRY., vol. 17, no. 4, 1980, PROVO US, pages 733 - 736 *

Cited By (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9463295B2 (en) 1996-07-26 2016-10-11 Resmed Limited Mask and mask cushion therefor
US6022884A (en) * 1997-11-07 2000-02-08 Amgen Inc. Substituted pyridine compounds and methods of use
US6184237B1 (en) 1997-11-07 2001-02-06 Amgen Inc. Substituted pyridine compounds and methods of use
US6333341B1 (en) 1997-11-07 2001-12-25 Amgen Inc. Substituted pyridine compounds and methods of use
US6458813B1 (en) 1997-11-07 2002-10-01 Amgen Inc. Substituted pyridine compounds and methods of use
US6362009B1 (en) 1997-11-21 2002-03-26 Merck & Co., Inc. Solid phase synthesis of heterocycles
US6903094B2 (en) 1998-03-26 2005-06-07 Japan Tabacco, Inc. Amide derivatives and nociceptin antagonists
US6410561B1 (en) 1998-03-26 2002-06-25 Japan Tobacco Inc. Amide derivatives and nociceptin antagonists
US7071180B2 (en) 1999-05-21 2006-07-04 Biovitrum Ab Certain arylaliphatic and heteroaryl-aliphatic piperazinyl pyrazines and their use in the treatment of serotonin-related diseases
JP4831903B2 (ja) * 1999-05-21 2011-12-07 プロキシマゲン・リミテッド 新規化合物、その使用および製造
US7534794B2 (en) 1999-05-21 2009-05-19 Biovitrum Ab Certain arylaliphatic and heteroaryl-aliphatic piperazinyl pyrazines and their use in the treatment of serotonin-related diseases
WO2000076984A2 (fr) * 1999-05-21 2000-12-21 Biovitrum Ab Nouveaux composes, et utilisation et preparation de ces derniers
US6465467B1 (en) 1999-05-21 2002-10-15 Biovitrum Ab Certain aryl-aliphatic and heteroaryl-aliphatic piperazinyl pyrazines and their use in the treatment of serotonin-related diseases
JP2003502317A (ja) * 1999-05-21 2003-01-21 ビオヴィトルム・アクチボラゲット 新規化合物、その使用および製造
KR100722090B1 (ko) * 1999-05-21 2007-05-25 바이오비트럼 에이비 신규 화합물, 이의 용도 및 이의 제조 방법
WO2000076984A3 (fr) * 1999-05-21 2001-02-08 Pharmacia & Upjohn Ab Nouveaux composes, et utilisation et preparation de ces derniers
EP2036564A1 (fr) 1999-12-06 2009-03-18 H.Lundbeck A/S Combinaison d'un inhibiteur du recaptage de la serotonine et d'un antagoniste, d'un agoniste inverse ou d'un agoniste partiel de 5-ht
FR2810979A1 (fr) * 2000-06-29 2002-01-04 Adir Nouveaux derives de diphenyluree, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
EP1170288A2 (fr) * 2000-06-29 2002-01-09 Les Laboratoires Servier Dérivés de diphenylurée et leur utilisation en tant qu'antagonistes alpha2/5-HT2c
EP1170288A3 (fr) * 2000-06-29 2002-01-16 Les Laboratoires Servier Dérivés de diphenylurée et leur utilisation en tant qu'antagonistes alpha2/5-HT2c
WO2002040457A1 (fr) 2000-11-20 2002-05-23 Biovitrum Ab Composes de piperazinylpyrazines utilises comme antagonistes du recepteur de la serotonine 5-ht2
US6756377B2 (en) 2000-11-20 2004-06-29 Biovitrum Ab Compounds and their use
US7067506B2 (en) * 2001-03-02 2006-06-27 Icos Corporation Compounds useful for inhibiting Chk1
US7608618B2 (en) 2001-03-02 2009-10-27 Icos Corporation Urea or thiourea substituted 1,4-pyrazine compounds useful as anti-cancer agents and for inhibiting Chk1
US7291603B2 (en) 2002-07-24 2007-11-06 Ptc Therapeutics, Inc. Nucleoside compounds and their use for treating cancer and diseases associated with somatic mutations
US7056925B2 (en) 2002-08-13 2006-06-06 Abbott Laboratories Urea kinase inhibitors
US9266883B2 (en) 2013-10-25 2016-02-23 Novartis Ag Ring-fused bicyclic pyridyl derivatives as FGFR4 inhibitors
US9533988B2 (en) 2013-10-25 2017-01-03 Novartis Ag Ring-fused bicyclic pyridyl derivatives as FGFR4 inhibitors
US9896449B2 (en) 2013-10-25 2018-02-20 Novartis Ag Ring-fused bicyclic pyridyl derivatives as FGFR4 inhibitors
US9802917B2 (en) 2015-03-25 2017-10-31 Novartis Ag Particles of N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-formyl-6-((4-methyl-2-oxopiperazin-1-yl)methyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide
US11858939B2 (en) 2015-07-06 2024-01-02 Alkermes, Inc. Hetero-halo inhibitors of histone deacetylase
US10421756B2 (en) 2015-07-06 2019-09-24 Rodin Therapeutics, Inc. Heterobicyclic N-aminophenyl-amides as inhibitors of histone deacetylase
US10919902B2 (en) 2015-07-06 2021-02-16 Alkermes, Inc. Hetero-halo inhibitors of histone deacetylase
US10696673B2 (en) 2017-01-11 2020-06-30 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US10793567B2 (en) 2017-01-11 2020-10-06 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US10519149B2 (en) 2017-01-11 2019-12-31 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US11225479B2 (en) 2017-01-11 2022-01-18 Alkermes, Inc. Bicyclic inhibitors of histone deacetylase
US11286256B2 (en) 2017-01-11 2022-03-29 Alkermes, Inc. Bicyclic inhibitors of histone deacetylase
US9951069B1 (en) 2017-01-11 2018-04-24 Rodin Therapeutics, Inc. Bicyclic inhibitors of histone deacetylase
US11987580B2 (en) 2017-01-11 2024-05-21 Alkermes, Inc. Bicyclic inhibitors of histone deacetylase
US11225475B2 (en) 2017-08-07 2022-01-18 Alkermes, Inc. Substituted pyridines as inhibitors of histone deacetylase
US11912702B2 (en) 2017-08-07 2024-02-27 Alkermes, Inc. Substituted pyridines as inhibitors of histone deacetylase

Also Published As

Publication number Publication date
JPH10508584A (ja) 1998-08-25
GB9420999D0 (en) 1994-12-07
EP0788499A1 (fr) 1997-08-13
US5866586A (en) 1999-02-02

Similar Documents

Publication Publication Date Title
US5866586A (en) CNS-active pyridinylurea derivatives
US5508288A (en) Indole derivatives as 5HT1C antagonists
US6025367A (en) Sulfonamide derivatives as 5HT7 receptor antagonists
WO1996011929A1 (fr) Derives biheteroaryl-carbonyles et carboxamides possedant une activite antagoniste de 5ht 2c/2b
WO1996002537A1 (fr) Carboxamides heterocycliques benzo-condenses a cinq elements utilises comme antagonistes de recepteur de 5ht¿2b/2c?
WO1994014801A1 (fr) Derives heterocycliques de l'uree antagonistes de 5ht2c et 5h¿2b?
WO1997008167A1 (fr) Antagonistes des recepteurs 5ht2c et 5ht¿2b?
US20050090496A1 (en) Sulphonyl compounds with 5-ht6 receptor affinity
NZ238141A (en) 1,2,3,4,4a,10b-hexahydro-6-(sulphonamidophenyl)benzo(c)(1,6)naphthyridine derivatives, preparation and pharmaceutical compositions thereof
EP0912556B1 (fr) Derives de l'indoline utiles comme antagonistes des recepteurs 5ht-2c
WO1994022871A1 (fr) DERIVES THIENO-INDOLIQUES UTILISES COMME ANTAGONISTES DE 5HT2c ET DE 5HT2b
EP0912554B1 (fr) Derives de l'indoline utiles comme antagonistes des recepteurs 5ht-2c
JP2000506877A (ja) アザスピロ誘導体
WO1998052943A1 (fr) Derives d'indoline comme antagonistes du recepteur 5ht¿2c?
WO1995021844A1 (fr) Indoles condenses a titre d'antagonistes des recepteurs de 5ht¿2b?
KR100486795B1 (ko) 5-ht-2c수용체길항제로유용한인돌린유도체

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1995934135

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 08817580

Country of ref document: US

WWP Wipo information: published in national office

Ref document number: 1995934135

Country of ref document: EP

WWR Wipo information: refused in national office

Ref document number: 1995934135

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1995934135

Country of ref document: EP